A complete set of fluorescent RNA nucleoside analogs gives researchers an improved tool for probing biophysical properties of nucleic acids, according to a new study (J. Am. Chem. Soc., DOI: 10.1021/ja206095a). Chemists Yitzhak Tor, Dongwon Shin, and Renatus W. Sinkeldam of the University of California, San Diego, synthesized all four analogs using the same thienopyrimidine core. The researchers obtained the pyrimidine analogs (cytidine analog shown) by adding d-ribose to N-1 of the heterocycle, and they synthesized the purine mimics (adenosine analog shown) by adding the sugar to C-2 of the thiophene. Synthetic modification furnishes hydrogen-bonding faces that match those of the natural RNA nucleosides. The nucleoside mimics fluoresce intensely, respond to their environment’s polarity, and maintain their fluorescence even after incorporation into RNA duplexes. “Use of the same thienopyrimidine skeleton for both the purine and pyrimidine analogs is clever and helps in synthetic accessibility,” says Eric T. Kool, a Stanford University chemistry professor who introduced his own set of size-expanded RNA analogs earlier this year (Org. Lett., DOI: 10.1021/ol102915f).